Detection and analysis of beta-catenin mutations in prostate cancer

BACKGROUND. E-cadherin and alpha -catenin are components of adherens juncti ons which mediate calcium-dependent, cell-cell adhesion in a homotypic mann er. Both these molecules have been defined as useful tumor markers as their altered expression correlates with increased tumor aggressiveness and dedi fferentiation. More recently, alterations of a third component of adherens junctions, beta -catenin, have been observed to play a role in several huma n cancers. Dysregulation of beta -catenin, either by direct mutation or by defects in inter acting pathways/regulators, can result in its cytoplasmic accumulation and nuclear translocation. In the nucleus, beta -catenin forms a transcriptional complex capable of upregulating target genes, many of wh ich encode proliferative factors. Given its oncogenic activity and connecti on to human cancer, we examined the beta -catenin gene and its expression i n prostate cancer. METHODS. By single-stranded conformational polymorphism (SSCP) and DNA sequ encing analyses, we screened exon 3 of beta -catenin from a panel of 81 pri mary tumors obtained at radical prostatectomy, 22 lymph node metastases fro m untreated patients, and a unique set of 61 metastatic tissues from 19 pat ients who died of hormone-refractory disease. RESULTS. We found putative activating mutations (missense and deletion) at a rate of 5% (7/138). One patient had the same 72 base pair deletion in eac h of nine separate metastases examined, indicating that this change was ass ociated with a clonal population of metastatic cells. CONCLUSIONS. Immunohistological staining of mutation-positive tumors demons trated beta -catenin accumulation and nuclear localization in a heterogeneo us fashion. Consistent with this in vivo finding, our in vitro analyses dem onstrate that certain mutations can result in increased beta -catenin nucle ar activity in prostate cancer cell lines. These data implicate the beta -c atenin signaling pathway in the development of a subset of prostate cancers . (C) 2000 Wiley-Liss, Inc.